The overall goal of this application is to test the feasibility of an IgE-guided, RNA interference (RNAi)-mediated, targeted silencing of the beta chain of the high affinity receptor for IgE (FcRIb) by small interfering RNA (siRNA) as a novel therapeutic to treat allergic diseases. With increasing prevalence in the past decades, allergies have now become a major public health problem worldwide. However, the treatment options for allergies remain very limited. The proposed novel therapeutic approach is a platform based on an IgE-guided RNAi strategy, targeting the critical gene for initiation and/or regulation of the allergic response, FceRIb, to attenuate the allergic response in basophils and mast cells for ultimate suppression of allergic diseases. To this end, the negatively charged siRNA molecules targeting for FceRIb expression silencing are complexed with the conjugates composed of the anti-IgE Fab fragment coupled to the positively charged cationic polymer polyethylenimine (PEI). Therefore, the Fab-PEI:siRNA complex can be highly effective for focusing onto the cell surfaces of the IgE-bound basophils/mast cells for targeted delivery. Due to the critical role as a potent amplifier for allergic response, targeted silencing of the FceRIb in allergic effector cellsis expected to attenuate the signaling cascade, resulting in the suppression of the allergic response. Thus we hypothesized that allergic responses can be blocked by targeted silencing of the FceRIb expression in the allergic effector cells. To test this hypothesis, in Aim 1 we will develop the optimal IgE-guided RNAi approach for targeted FceRIb silencing in basophils/mast cells as a novel strategy for suppression of allergic responses in vitro in cell culture based models. We will refine and determine the optimal conditions for maximal RNAi knockdown effects on FceRIb expression in basophil/mast cells and determine the outcome of FceRIb expression silencing on inhibition of allergic response in vitro. In Aim 2, we will test the therapeutic effects of the targeted FceRIb knockdown mediated by IgE-guided RNAi to block the allergic response in three different animal models. This application will likely lead to the development of a novel siRNA-based approach for the treatment and prevention of allergic diseases.